Human growth hormone (hGH) is a non-glycosylated peptide hormone secreted by the eosinophil of human anterior pituitary. hGH has various biological functions, such as influencing the metabolism of sugars, proteins and lipids, and directly influencing the proliferation, differentiation and DNA synthesis of some cells, but the main function is stimulating body growth, including skeletons, muscles, connective tissues, hair and skin. Recombinant Human Growth Hormone (rhGH) is a hydrophilic protein, which comprises two kinds of molecules with different sizes. The molecular weight of the main component is 22 Kda, and the isoelectric points is 4.9, containing 191 amino acid residues, and 4 Cys residues consisting two pairs of disulfide bonds which formed two peptide cycles with different sized. The molecular weight of the rest component of 5%˜10% human growth hormone is 20 Kda, containing 176 amino acid residues with lacking 15 amino acid residues on 32˜46 positions of 22 Kda recombinant human growth hormone.
In recent years, genetic engineering technology has been applied to produce large quantities of recombinant human growth hormone, which has promoted the research on growth hormone and broadened its clinical application. The usage range expanded from limited to treat the children with pituitary dwarfism whose growth is seriously inhibited originally to treat other diseases. Human growth hormone is mainly used to treat the following diseases:
1) Children with GH defect or other diseases accompany with growth inhibition
Some diseases may cause GH defect during treatment thus influence growth, such as cerebroma, craniopharyngioma and leukemia. When used Lateral cephalogram radiotherapy or whole body radiotherapy to the patients suffered those diseases, which will cause GH defect to influence growth. Treatment with rhGH can make patients to keep growing, but the children patients without treatment can not recover automatically from the GH defect induced by radiotherapy. As to the children suffered from the neuroblastoma, GH is also an effective stimulus for the growth.
Some diseases, such as Turner's Syndrome, Down's Syndrome, also can arose growth inhibition and other symptoms, but the GH level of patients is not obviously abnormal, and GH administration can lessen the symptoms.
2) metabolism change
GH has specific effect on lipid, glucose and protein metabolism. For the children, adults and elders with GH relative defect, it can influence their various metabolism parameters effectively.
3) osteoporosis
GH can increase chondrocytes proliferation, osteoblasts proliferation and activity. GH also can enhance bone function by increasing the calcium absorption from intestines.
4) Functional renal failure
GH can enhance renal function and rescue the growth inhibition due to chronic renal failure.
5) reproductive malfunction
GH is the permissive factor of various gonadotropin hormones, which indicates that GH can be used to treat male or female infertility.
6) Burn
Recently, as GH has the actions of indirectly promoting growth and enhancing metabolism, increasing cellular and humoral immune response and reducing stress response, it has been widely used in treating clinical burn patients, improving postoperative patients' immunity and speeding up wound healing.
Granulocyte macrophage Colony stimulating Factor (GM-CSF) is differentiated from marrow, and separated from bone marrow precursors, with the biological function of stimulating the colony-forming of macrophagocyte and granulocyte. GM-CSF can also stimulate mature macrophagocyte, eosinophil and neutrophil to induce various functional activities. GM-CSF is an acid protein, and has high affinity with the receptor of GM-CSF sensitive cell.
GM-CSF is a kind of acid protein that is produced and secreted by T cell, B cell, macrophagocyte, mastocyte, endothelial cell and fibroblast and so on. Mature rhGm-CSF comprises 127 amino acids, which comes from cutting off signal peptides of 17 amino acids on the protein precursor with 144 amino acids. Its relative molecular weight is 147000 Da and biological activity can resist to glycosylation.
In recent years, as the application of genetic engineering technology is used to produce large quantities of rhGM-CSF, it has promoted the research on growth hormone and broadened its clinical application. It is the most well known by clinical investigators and the product of it is in the market among diversified cell factors. The basic function of GM-CSF is to stimulate the hemopoietic stem cells to proliferate and differentiate the granulocytes and macrophagocyes, and GM-CSF then matures to have phagocytic function. However, the clinical applications of GM-CSF are not so limited but related to many fields.
So far, the applications of rhGM-CSF now include the following aspects:
(1) Application on rhGM-CSF in tumor disease treatment
1) Solid tumor diseases: In clinic, most tumor chemotherapy drugs will increase the toxicity to the marrow hematopoietic function with the dose increase, result in neutrophil granulocyte decrease and infection increase. Researchers have proven that the neutropenia period could be shortened and the infection rate could be declined by additionally using GM-CSF after chemotherapy. At the same time, GM-CSF can induce and enhance the activity of peripheral monocyte macrophage cells killing tumor cells.
2) Leucocythemia: GM-CSF can prompt more interleukin progenitor cells into the cell cycle, which can shorten the duration of chemotherapy patients neutropenia period, increase the killing effect of chemotherapy drugs on leukemia cells, and reduce fever and infection complications.
(2) Aplastic anemia: The use of GM-CSF in aplastic anemia treatment will reduce the patient infection rate by 50%.
(3) Application on GM-CSF in bone marrow transplantation
GM-CSF can accelerate hematopoietic function recovery, significantly accelerate WBC and PMN recovery, lower infection rate and reduce the times of antibiotic infusion so as to reduce hospitalization time; Meanwhile, through the application of rhGM-CSF and other cytokines, the normal hematopoietic stem cell growth can be regulated and promoted.
(4) Application on GM-CSF in anti-infection treatment
As GM-CSF can stimulate hemopoietic stem cells differentiation to granulocyte and macrophage and proliferate the same, and then gradually mature as phagocytosis cells. It can collaborate with clinical treatment of infectious diseases; In addition, during the bacteremia infection and the spread processes of AIDS patients (mycobacterium invade into monocytes macrophages), the use of GM-CS can activate the infected macrophages, thereby inhibit or kill the mycobacterium in cells with synergistic effect of antibiotic treatment.
Based on the plenty of basic and clinical research results, GM-CSF has bright prospects for clinical application as follows:
(1) GM-CSF has the effect of promoting healing of wounds
Animal experiments show that GM-CSF can induce fibroblasts proliferation and the typical muscle cells formation; activate neutrophils and monocytes/macrophages, prompt endothelial cell mitosis and migration, promote the proliferation of keratinocytes and regulate the expression of fibroblasts. Therefore, it plays a very important role in the promotion of wound healing process.
(2) According to the effect characteristics of GM-CSF on the cell cycle and chemotherapy cycle, the application of the cytokines thereby
GM-CSF has effects on all growth levels cells in hematopoietic system, therefore, using the application of GM-CSF at a suitable time during chemotherapy periods can significantly reduce toxicity of chemotherapy and enhance the effects of chemotherapy.
(3) GM-CSF's Immunopotentiation Effects
Numerous experiments show that GM-CSF is a high efficiency immune adjuvant, it can enhance the immune response to vaccine (antigen) of the body, so as to strengthen the body's immune resistance to disease through five ways including systemic actions, regional applications, local application, the fusion protein and in vitro cell activation antigen expression.
GH and GM-CSF have special physical and chemical properties, such as being easily decomposed in intestine, and are used as injection in clinical treatment. So far, no external preparation made of rhGH and rhGM-CSF is used in the treatment of various lesions and ulcers, especially in corneal lesion and corneal ulcer.